DESCRIPTION (Applicant's Abstract): Cholinesterases are known to be present in mammalian heart tissue. However, the distribution of these enzymes is controversial. Some investigators reported that acetylcholinesterase is present only in intracardiac nerves, while others have suggested that it is also associated with myocytes. Recent studies with isolated myocytes have now established that AChE is found in the myocyte itself. However, it is evident that AChE is only a minor component of cardiac ChEs and that, unlike other striated muscle, the heart contains primarily butyrylcholinesterase. It is not clear why this muscle has such a high density of BuChE. Physiological roles of this enzyme are not well understood. It would seem likely that hydrolysis of acetylcholine is not the major role for BuChE. Some investigators have suggested that BuChE may play a role in lipid metabolism or in detoxifying products of lipid metabolism. This function is consistent with the high density distribution of BuChE in heart, liver and adipose tissue where lipids are preferred energy sources. Other projected roles of BuChE include metabolism of xenobiotics and peptidase activity. Which of these roles are of physiological significance may depend on the subcellular location of the enzyme in cardiac myocytes. Yet virtually nothing is known of the location of this enzyme in heart. Indeed, little is known of the subcellular distribution of AChE in cardiac cells. The current proposal will examine the solubility characteristics and subcellular distribution of these enzymes using contemporary biochemical techniques of differential solubilization and, centrifugation in order to gain a better understanding of how distribution of these enzymes in cardiac myocytes might contribute to their functions. Furthermore, this project will investigate the potential protective role of this enzyme against xenobiotics by examining the relationship of BuChE to cocaine cardiotoxicity. While it is clear that plasma BuChE can hydrolyze cocaine, it is not known if the cardiac enzyme significantly metabolizes this drug. If cardiac BuChE plays a major role in metabolizing cocaine, it is possible that individuals with genetically determined atypical BuChE or reduced BuChE activity (due to drugs or poisons) may show enhanced cardiac morbidity from toxic esters such as cocaine.